There is a growing body of preclinical evidence supporting the activity of ATO in the treatment of infiltrating astrocytomas. Early reports demonstrated the antiproliferative effect of ATO on cell cycle progression.14,15
Subsequently, preclinical studies have shown the augmented impact of arsenic when given with radiation therapy.12,16,17
Numerous publications have addressed the possible mechanisms of ATO-induced cell death in malignant glioma cells.13,18–24
Further studies on the benefit of chemoradiotherapy with ATO have demonstrated an enhanced induction of autophagy through inhibition of phosphoinositide-3 kinase/Akt and activation of extracellular signal-regulated kinase 1/2 signaling pathways.16
This study confirmed the safety and tolerability of ATO given at a dosage of 0.15 mg/kg/day when administered concomitantly with focal radiotherapy for the treatment of infiltrating astrocytomas in children. No significant cardiac toxicities were noted. The therapy was well tolerated with modest toxicities, many of which are commonly attributed to irradiation alone. The study was originally designed to allow for dose escalations above 0.15 mg/kg on each day of radiotherapy but was amended following the report by Fox et al8 that reported a recommended daily dose of 0.15 mg/kg of ATO due to dose-limiting QTc prolongation or pancreatitis when the dosage was raised to 0.2 mg/kg/day in children with leukemia. Whether a higher dose of ATO administered in this study would be more efficacious during chemoradiotherapy is unknown. Of note, pharmacokinetic determinations were not undertaken in this trial, although given the identical dose levels, they would not be anticipated to differ from the results reported by Fox et al.
An additional area of uncertainty relates to the optimal time of ATO infusion in relation to the administered dosage of therapeutic radiation. This study allowed for the administration of ATO either before or after planned daily radiation therapy in an effort to address the complexity of daily infusions and irradiation, particularly for children requiring anesthesia for daily radiation therapy. A report by Ning and Knox25
published in 2006 suggested that, at least in their preclinical model, ATO administration was most effective at 0–4 h after radiation therapy.25
A more recent in vitro study suggested that pretreatment with ATO prior to administration of temozolomide, bevacizumab, and ionizing radiation led to fewer cells in G0
, suggesting the potential to increase sensitivity to other chemotherapeutics and radiotherapy.26
While not mandated by the study, ATO was administered in advance of the daily dose of therapeutic radiation in 19 of 21 subjects. There were insufficient numbers of subjects who received post–external beam radiotherapy ATO to draw any in vivo conclusions.
A number of recent studies provide some additional observations that may have future therapeutic relevance. A variety of preclinical studies have demonstrated that ATO has a direct inhibitory effect on cancer stem-like cells. Mechanisms of this inhibition of cancer stem-like cells include deregulation of Notch inhibition27
and downregulation of Sox2.6
Hints to possible combinatorial therapies have been published, including combination with inhibitors of tumor necrosis factor–related apoptosis-inducing ligand,28
of heat-shock protein,29
and of heme oxygenase-1.30
An additional observation, relevant to the management of patients with infiltrating astrocytomas, medulloblastoma, and other solid tumors, is the finding first reported by Kim et al31
that ATO antagonizes the hedgehog pathway at the level of the Gli2 transcriptional effector.31
have substantiated this finding. These findings raise the possibility that for particular tumor types, such as Sonic hedgehog–driven medulloblastoma, the use of ATO chemoradiotherapy might provide more targeted treatment than other chemotherapeutics, such as vincristine, that have been traditionally used during chemoradiotherapy.
In conclusion, ATO administered daily during delivery of radiation therapy is well tolerated, with minimal side effects. Given the low toxicity, coupled with a growing body of evidence regarding the mechanism of ATO-induced cytotoxicity, ATO may be an ideal agent for further combinatorial radiotherapy in the treatment of infiltrating astrocytomas and other pediatric solid tumors.